COLON CANCER Clinical Colorectal Cancer

1. Epidemiology

Abby Siegel MD, MS

2. Risk factors 3. Manifestations 4. Treatment

1. EPIDEMIOLOGY

Colorectal Cancer Incidence, 2008

- Colorectal cancer is the third mostt common cancer in i the th United States - About 150,000 new cases/year - Most cases in people over 50

Colorectal Cancer Deaths, 2008

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EPIDEMIOLOGY - Incidence rates high in U.S., Europe, Australia - Increasing in Japan - Low in China, Africa

EPIDEMIOLOGY - Changes in incidence rates over time and with migration may indicate role of environmental factors

NSAIDS 1) Cox-1 and Cox-2 inhibition -Aspirin, Ibuprofen -Bleedingg risk 2) Selective Cox-2 inhibition -Rofecoxib (Vioxx), -Celecoxib (Celebrex) -Thrombosis risk

2. RISK FACTORS: Protective - Folic acid - Exercise - NSAIDS - ? Calcium/Vitamin D - ? Fiber

RISK FACTORS: Increased risk with… -Advanced age -Inflammatory Inflammatory bowel disease -Consumption of high-fat diet -Personal or family history of colon cancer

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FAMILIAL SYNDROMES

• 2-5% of colon cancers • Caused by mutations in mismatch repair genes • Tend to ppresent in the right g colon • Often associated with endometrial cancer in women • Start screening at age 21

• HNPCC – Hereditary non-polyposis colon cancer

• APC – Adenomatous polyposis coli

• Both usually autosomal dominant

HNPCC Increases the Risk of Colorectal Cancer By age 50

0.2%

2%

HNPCC Risk

>25%

80%

By age 50

Gastroenterology 1996;110:1020 1996;110:1020--7 Int J Cancer 1999;81:214 1999;81:214--8

HNPCC: Cancer Risks 100 % with cancer

Colorectal 78%

60 Endometrial 43%

40

Stomach 19% Biliary tract 18% Urinary tract 10% Ovarian 9%

20 0 0

20

40 60 Age (years)

HNPCC Increases the Risk of Endometrial Cancer

By age 70

Population Risk

80

HNPCC (Lynch Syndrome) Hereditary Non-Polyposis Colon Cancer

80

By age 70

Population Risk

0.2%

1.5%

HNPCC Risk

20%

60% Gastroenterology 1996;110:1020 1996;110:1020--7 Int J Cancer 1999;81:214 1999;81:214--8

APC Adenomatous Polyposis Coli • Less than 1% of colon cancers • Caused by mutation of APC gene (5q21) • Also associated with duodenal cancers, desmoid tumors, “CHRPE” (congenital hypertrophy of the retinal pigment epithelium) • Start screening at puberty

Aarnio M et al. Int J Cancer 64:430, 1995

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3. MANIFESTATIONS 1. Growth of cancer at primary site 2. Metastatic spread

MANIFESTATIONS 1. Growth of cancer at primary site a. Asymptomatic/screening b. Right sided syndrome c. Left sided syndrome

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Virtual Colonoscopy

MANIFESTATIONS 1. Growth of cancer at primary site i. Asymptomatic - Detected by screening test - Fecal occult blood - Sigmoidoscopy - Colonoscopy - “Virtual” colonoscopy - Molecular techniques

Pickhardt et al. NEJM, 349 (23): 2191, 2003

Screening summary

Screening, continued…

• Average risk: colonoscopy every 10 years over age 50 • Family F il history: hi t colonoscopy l 10 years before index case • Dysplastic polyps: repeat colonoscopy after 3 years

• APC: annual flexible sigmoidoscopy starting at age 11, colectomy when polyps develop p • HNPCC: colonoscopy at age 21, then every 1-2 years • Inflammatory bowel disease: start 8 years after pancolitis, 12 years after distal disease

MANIFESTATIONS 1. Growth of cancer at primary site ii. Right sided syndrome a) Ascending colon has thin wall, wall large diameter, distensible b) Liquid fecal stream c) Chronic blood loss results in iron deficiency anemia*** d) Obstruction unlikely

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“Apple core lesion”

MANIFESTATIONS 1. Growth of cancer at primary site iii. Left sided syndrome a) Descending colon wall thicker, less distensible b) More solid fecal stream c) Tumors tend to infiltrate d) Bright red blood more common e) Obstruction more common

COMPARISON RIGHT AND LEFT SIDED COLON CANCERS Right

Left

Anemia

+++

+

Occult bleeding

+++

+

+

+++

Gross bleeding Abd. Mass Change in bowel habits Obstruction

++

+

+

+++

+

+++

Stage 1 Colorectal Cancer • 23% of colorectal CA • Cancer has grown through the mucosa and invades the muscularis • Treatment: surgery to remove the tumor and some surrounding lymph nodes • Survival: 93% Adapted from www.plwc.org, 2007

Stage 2 Colorectal Cancer

Stage 3 Colorectal Cancer

• 31% of colorectal CA • Cancer grows beyond the muscularis of the colon or rectum ectu but has as not ot spread sp ead to the lymph nodes • Treatment (colon): surgery +/-- adjuvant chemotherapy +/ • Survival: 72 to 85% • Treatment (rectal): surgery, radiation and chemo Adapted from www.plwc.org, 2007

• 26% of colorectal CA • Cancer has spread to the regional lymph nodes • Treatment (colon): surgery s rger and adjuvant chemotherapy • Survival: 44 to 83% • Treatment (rectal): surgery, radiation and chemotherapy Adapted from www.plwc.org, 2007

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Stage 4 Colorectal Cancer • 20% of colorectal CA • Cancer has spread to other areas of the body • Treatment: chemotherapy. C id surgery off Consider primary lesion, especially if symptomatic • Surgery to remove metastases (liver/lung) in carefully selected patients • Survival: 8%

PROGNOSIS depends on… 1. Histological features - poor differentiation -vascular invasion 2. Depth of invasion 3. Nodal involvement 4. Genetic alterations -18q LOH (bad), MSI (good), K-ras mutation (limits response to anti-EGFR antibodies)

Source: UpToDate.com, 2007

MANIFESTATIONS Metastatic Spread 1. Lymphatics Mesenteric nodes Virchow’s node 2. Hematogenous spread Liver via portal circulation

LIVER METASTASES MANIFESTATIONS 1. Pain ((stretchingg capsule) p ) 2. Hepatomegaly, nodularity 3. Elevated liver function tests

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TREATMENT: Pharmaceuticals

4. TREATMENTS 1. Surgery -Localized disease (Stage I, II, III) -Try to remove isolated metastases 2. Radiation therapy -Rectal cancer-helps prevent local recurrence 3. Pharmaceuticals -Stage III and IV disease

1. 5-Fluorouracil - pyrimidine antimetabolite 2. Irinotecan - topoisomerase inhibitor prevents re-ligation after cleavage of DNA by topoisomerase I 3. Oxaliplatin - alkylating agent, causes formation of bulky DNA adducts

Exciting new biologics…

EGFR inhibition and rash

• • • • •

Bleeding Thrombosis Hypertension Wound healing complications Half life about 3 weeks; wait at least 2 halflives before major surgery

Correlating Survival With Skin Rash P = .0008*

P = .0007*

14 12

P = .04* 10

Surviva al

4. Bevacizumab -Antibody against VEGF -May block angiogenesis and also stabili e leaky stabilize leak vasculature asc lat re 5. Cetuximab, Panitumomab -Antibodies against EGFR -Binds to EGF receptor on tumor cells, prevents dimerization and cell signaling

Bevacizumab toxicities

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G0 G1 G2 G3

P = .0002* 0002*

6 4 2 0 9923/CRC

0141/CRC

9816/SCCHN

9814/Pancreas

* Log-rank P value, grade 0 vs. grades 1-3 Saltz L et al. Proc Am Soc Clin Oncol 2003; 22:204 (abstract 817) Slide courtesy of Josep Tabernero, MD

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Molecularly Targeted Therapy in Oncology

VEGF

Cetuximab, Panitumomab

Original Article

Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer Eric Van Cutsem, M.D., Ph.D., Claus-Henning Köhne, M.D., Erika Hitre, M.D., Ph.D., Jerzy Zaluski, M.D., Chung-Rong Chang Chien, M.D., Anatoly Makhson, M.D., Ph.D., Geert D'Haens, M.D., Ph.D., Tamás Pintér, M.D., Robert Lim, M.B., Ch.B., György Bodoky, M.D., Ph.D., Jae Kyung Roh, M.D., Ph.D., Gunnar Folprecht, M.D., Paul Ruff, M.D., Christopher Stroh, Ph.D., Sabine Tejpar, M.D., Ph.D., Michael Schlichting, Dipl.Stat.,, Johannes S J Nippgen, ppg , M.D.,, and Philippe pp Rougier, g , M.D.,, Ph.D.

PDGFR

Sunitinib Sorafenib

P P

P P

Bevacizumab VEGFR

EGFR

P P

P P

P

P

P

Sunitinib Sorafenib

P

P13K STAT AKT

Ras

Gefitinib Erlotinib

Sorafenib

Raf

mTOR Mek

CCI-779 RAD001

HIF-1α HIF-1β

Transcription Factors Nucleus

N Engl J Med Volume 360(14):1408-1417 April 2, 2009

Survival/ ↓ Apoptosis

Angiogenesis

Cell proliferation

Metastases

Slide courtesy of Wells Messersmith, MD

Hazard Ratios for Progression-free and Overall Survival and Odds Ratios with Tumor Response, According to the Mutation Status of KRAS in the Tumor

Molecularly Targeted Therapy in Oncology

VEGF

Cetuximab, Panitumomab PDGFR

Sunitinib Sorafenib

P P

P P

Bevacizumab VEGFR

EGFR

P P

P P

P

P

P

Sunitinib Sorafenib

P

P13K STAT AKT

Gefitinib Erlotinib

Ras Raf

Sorafenib

mTOR

CCI-779 RAD001

Mek HIF-1α HIF-1β

Transcription Factors Nucleus

Van Cutsem E et al. N Engl J Med 2009;360:1408-1417

Survival/ ↓ Apoptosis

Angiogenesis

Metastases

Cell proliferation

Slide courtesy of Wells Messersmith, MD

TREATMENT Pharmaceuticals 1. “Adjuvant” (after surgery) Curative goal in patients after complete l t resection ti 2. Palliation in patients with gross metastatic disease 3. “Neoadjuvant” (before surgery) Shrink tumors, then try to resect in limited metastatic disease

TREATMENT: Metastatic disease • Systemic chemotherapy now has improved survival for those with metastatic disease to about 2 years • We now sometimes treat neoadjuvantly (before surgery), shrinking metastases and then surgically removing them • This is important, because some of these “limited metastases” patients are cured!

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Trends in the Median Survival of Patients with Advanced Colorectal Cancer

Estimated drug costs for eight weeks of treatment for metastatic colorectal cancer 30000 25000 20000 15000

Cost in $

10000 5000 0 5FU

Combo

Antibody

Meyerhardt, J. A. et al. N Engl J Med 2005;352:476-487 Schrag, D. N Engl J Med 2004;351:317-319

Conclusions: • Know HNPCC and APC—these may help you prevent cancers in others • Understand how colon cancer commonly presents ((right g versus left-sided), ), and common sites of spread • Think about colon (or other GI) cancer in an older person with iron-deficiency anemia—don’t just give them iron! • Don’t give up on those with metastatic disease with new treatment options and occasionally cures

• My email: • [email protected] • Many thanks to Tom Garrett for many slides!

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